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Pre-clinical Investigational Data About Novel Conditionally Active Biologics to be Presented at AACR

At the end of March, the annual meeting of the American Association for Cancer Research (AACR), to be held March 29 – April 3, 2019, is expected to covers the latest discoveries across the spectrum of cancer research—from population science and prevention to cancer biology, as well as translational research and clinical studies.

The annual meeting will also included updated about survivorship and advocacy, and highlights the work of the best minds in research and medicine from institutions all over the world.

Among the latest research results to be presented during the upcoming AACR meeting are pre-clinical data on BA3071, a novel conditionally active CTLA-4 inhibitor.

The CTLA-4 pathway is a key immune checkpoint pathway that provides a downregulating signal to T cells. Although inhibition of CTLA-4 has been shown to significantly improve the antitumor response, it may also lead to immune attack of healthy cells. To minimize on-target off-tumor toxicity, BioAtla applies its proprietary CAB technology with the intent to activate binding to the CTLA-4 receptor preferentially on T cells in the tumor microenvironment.

The data to be presented at AACR indicate that the company’s CAB-CTLA-4 molecule may have a superior safety profile when used in combination with PD-1 inhibitors and allow increased dosing levels to achieve superior efficacy to current anti-CTLA-4 therapy as a single agent or in combination with other anti-cancer therapies including immuno-oncology agents.

The BA3071 IND filing is planned for mid-2019. A Phase I/II multi-center, open-label study designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and antitumor activity of BA3071 alone and in combination with a PD-1 inhibitor is anticipated to start in later in 2019.

The second investigational agent is BA3181, a novel conditionally active EpCAM targeted antibody-drug conjugate or ADC (CAB-EpCAM-ADC), being developed by San Diego-based biopharmaceutical company BioAtla®.

EpCAM is expressed at high levels exclusively in epithelia and epithelial-derived neoplasms, making it a suitable target for many important solid tumor types and cancer stem cells. EpCAM expression on normal tissues limits its utility as a target for therapeutic antibodies and ADCs due to the potential effects on normal epithelial throughout the body. Using our CAB technology, BioAtla has developed CAB antibodies to EpCAM that reversibly bind to recombinant EpCAM and EpCAM expressing cells under select conditions that are present in the tumor microenvironment but not in normal tissues.

In vitro and in vivo efficacy data for several anti-EpCAM antibodies and ADCs will be presented and suggest that conditionally active EpCAM ADCs generated using the CAB technology provided drug candidates, including BA3181, that have the potential to have an increased safety margin and therapeutic index in the clinic.

Development programs
The company’s novel CAB-CTLA-4 and CAB-EpCAM-ADC programs are designed to yield conditionally active therapeutics (antibodies as well as other biologics) that can be activated or inactivated under defined physiological conditions (e.g., pH, oxidation, temperature, pressure, presence of certain ions, hydrophobicity and combinations thereof) both outside and inside cells.

The company’s patented Conditionally Active Biologics™ (CAB) technology takes advantage of the unique microenvironment associated with different diseases and tissues.

These differences can, for example, result from differences in metabolism between diseased and normal, healthy, tissue.

For example, in cancer the unique cell metabolism described by Otto Warburg, referred to as the “Warburg effect” (i.e., anaerobic glycolysis in the presence of oxygen in tumor cells) [*] contributes to a characteristic microenvironment that activates antibodies when they are in close proximity to a tumor, and reversibly inactivates an antibodies if they drift away from the tumor.

Compelling data
“These new data showcase the capabilities of our proprietary CAB technology, which we believe will expand the number of druggable protein targets and maximize both potency and safety in combination therapies, antibody drug conjugate (ADC) medicines, bispecifics and other targeted therapy formats for cancer treatments,” explained Jay M. Short, Ph.D., Chairman, Chief Executive Office and co-founder of BioAtla.

“We are particularly excited by these new preclinical data for our novel CAB-CTLA-4 program as a single-agent or in combination with checkpoint inhibitors. This novel CAB has the potential for an improved safety margin and therapeutic index thereby improving this important cancer therapy,” added Scott Smith, President of BioAtla.

“These preclinical data suggest that our CAB technology may effectively address the issue of on-target off-tumor toxicity and allow leveraging the widely expressed and promising EpCAM target for cancer therapy,” Smith further noted.

In addition to the above programs, BioAtla has two programs currently in Phase I/II clinical trials, BA3011 a novel conditionally active AXL-targeted antibody-drug conjugate (CAB-AXL-ADC) and BA3021 a novel conditionally active ROR2-targeted antibody-drug conjugate (CAB-ROR2-ADC).

Abstract 19-A-6330
Title Potent CAB CTLA-4 antibody to reduce immune side effects and toxicities associated with single agent and combination cancer immuno therapies
#No 6215
Session Rational Combinations of Immunotherapy
Date/Time/Location April 1, 2019 / 3:00PM – 5:00 PM
Presenter William Boyle, Ph.D.
Title Novel conditionally active biologic (CAB) antibody targeting EpCAM demonstrates anti-tumor efficacy in vivo
#No 356
Session New Anticancer Agents
Date/Time/Location March 31, 2019 / 1:00 PM – 5:00 PM / Exhibit Hall B, Poster Section 14 / Poster Board Number: 17

[1] Otto AM. Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism. Cancer Metab. 2016 Mar 8;4:5. doi: 10.1186/s40170-016-0145-9. eCollection 2016. [PubMed][Article]

[*] In 1972 Efraim Racker, in his publication on the bioenergetics of tumor growth coined the presence of high aerobic glycolysis in tumors as the ‘Warburg effect’.

Last Editorial Review: Match 2, 2019

Featured Image: Annual Meeting AACR. Courtesy: © 2010 – 2019 AACR. Used with permission.

Copyright © 2010 – 2019 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.


FDA Clears Investigational New Drug application for BA3011, a Novel CAB-AXL-ADC Therapeutic

The U.S. Food and Drug Administration has cleared the Investigational New Drug Application (IND) for BA3011, a novel conditionally active AXL-targeted antibody-drug conjugate (CAB-AXL-ADC) being developed by BioAtla.

The novel, investigational agent is being developed for the treatment of patients with solid tumors.

Under this Investigational New Drug Application, the company intends to initiate a first-in-human, open label, multicenter, dose escalation and dose expansion study of CAB-AXL-ADC in patients with locally advanced or metastatic solid tumors.

CAB-AXL-ADC will be BioAtla’s first CAB investigational product to enter clinical trials in the United States.

The AXL receptor tyrosine kinase is often highly expressed in several cancer types that can lead to poor prognosis. A principal role of AXL appears to be in sustaining a major mechanism of resistance to diverse anticancer therapies. In addition, AXL is a factor in the repression of the innate immune response which may also limit response to treatment including immuno-oncology (IO) therapy.

Attractive target
While this makes the AXL receptor an attractive target for tumor therapy, the AXL receptor is also prevalent in normal tissue of several organs in the body. To minimize on-target-off-tumor toxicity of binding to AXL receptors on normal cells, BioAtla applies its proprietary CAB technology to develop its CAB antibody-drug conjugate or ADC targeting AXL with the intent to activate binding to the AXL receptor only in the tumor microenvironment and deliver the cytotoxic payload to the cancerous cells.

Warburg Effect
Conditionally Active Biologic or CAB proteins are generated using proprietary protein discovery, evolution and expression technologies developed BioAtla.

These proteins can be monoclonal antibodies, enzymes and other proteins designed with functions dependent on changes in microphysiological conditions (e.g., pH level, oxidation, temperature, pressure, presence of certain ions, hydrophobicity and combinations thereof) both outside and inside cells.

Studies have shown that cancerous tumors create highly specific conditions at their site that are not present in normal tissue. These cancerous microenvironments are primarily a result of the well understood unique glycolytic metabolism associated with cancer cells, referred to as the Warburg Effect, a process that includes increased glucose uptake and fermentation of glucose to lactate.

An essential process for sustaining mammalian life is the metabolism of glucose, a central macronutrient. This process allows for energy to be harnessed in the form of Adenosine triphosphate or ATP through the oxidation of its carbon bonds.[1]

In this process, glucose is concerted to pyruvate ** via glycolysis in the cytoplasm and then use pyruvate in oxygen-consuming mitochondria to produce carbon dioxide and ATP.

However, the development of cancer is, in part, based on the reprogramming of cellular energy metabolism to more effectively support the proliferation of neoplastic diseases.[2]

Depriving tumor cells of energy
Named after Otto Warburg, the Warburg Effect is based on the concept that by depriving tumor cells of glucose and oxygen, tumor cells are deprived of energy. In turn, by depriving the tumor cells of energy, Warburg and his colleagues observed that tumor cells were no longer able to rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance, and, as a result, would die.

Herbert Crabtree, another biochemist, further extended Warburg’s research. He discovered that, perhaps because of environmental or genetic influence, there is variability in fermentation as well as aerobic glycolysis.

Warburg believed that dysfunctional mitochondria is the source of anerobic glycolysis, which, he hypothesized, is the source of cancer. This phenomenon is observed even in the presence of completely functioning mitochondria.

Conditionally Active Biologics
Conditionally Active Biologics or CAB proteins are designed to deliver their therapeutic payload and/or recruit the immune response in specific and selected locations and conditions within the body and to be active only in the presence of a particular cellular microenvironment.

In addition, the activation is designed to be reversible to repeatedly switch ‘on and off’ should the CAB move from a diseased to a normal cellular microenvironment and vice versa. CABs can be developed in a variety of formats including antibodies, antibody-drug conjugates (ADCs), bi-specifics, chimeric antigen receptor T-cells (CAR-Ts) and combination therapies.

** When the oxygen is insufficient, pyruvate is broken down anaerobically, creating lactate in animals (including humans) and ethanol in plants. It is commonly encountered as one of the end products of glycolysis, which is then transported to the mitochondria for participating the citric acid cycle.

Last Editorial Review: January 30, 2018

Featured Image: Research Courtesy: © 2010 – 2017 Fotolia. Used with Permission.

Copyright © 2010 – 2018 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.


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